Comparative Toxicogenomic Responses to the Flame Retardant mITP in Developing Zebrafish

Area of Science:

• Environmental Toxicology
• Developmental Biology
• Molecular Toxicology

Background:

• Monosubstituted isopropylated triaryl phosphate (mITP) is a key component of Firemaster 550, a flame retardant used in polyurethane foams.
• mITP is the most toxic component of Firemaster 550, causing developmental cardiotoxicity, including pericardial edema and heart looping failure in zebrafish.
• While mITP is an aryl hydrocarbon receptor (AhR) ligand, its cardiotoxic effects are AhR-independent.

Purpose of the Study:

• To identify transcriptional signatures mediating mITP-induced cardiotoxicity, independent of the AhR.
• To compare transcriptomic responses to mITP in wild-type and ahr2-null zebrafish.
• To elucidate the molecular mechanism underlying mITP's developmental cardiotoxicity.

Main Methods:

• Comparative whole genome transcriptomics in wild-type and ahr2 mutant zebrafish exposed to mITP.
• Gene ontology enrichment analysis to identify affected biological processes.
• Gene-gene interaction network analysis to explore regulatory relationships.

Main Results:

• mITP exposure decreased expression of genes involved in all-trans-retinoic acid synthesis and Hox genes, irrespective of ahr2 status.
• Unique transcriptomic enrichments in wild-type zebrafish included xenobiotic metabolism and response to external stimuli.
• Overlapping transcriptomic changes in both genotypes involved retinoid metabolism and sensory perception, with evidence of cross-talk between AhR, Nrf2, and Hif1α pathways.

Conclusions:

• mITP's cardiotoxicity is mediated by inhibition of retinoic acid receptors (RARs), not through the AhR pathway.
• Transcriptomic analysis revealed significant alterations in retinoid metabolism and sensory perception pathways.
• The study provides evidence supporting a novel mechanism of mITP-induced developmental cardiotoxicity involving RAR inhibition.